2. Academic Validation
  3. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA

Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA

  • J Allergy Clin Immunol. 2015 Jan;135(1):217-27. doi: 10.1016/j.jaci.2014.10.019.
Louis-Marie Charbonnier 1,  Erin Janssen 1,  Janet Chou 1,  Toshiro K Ohsumi 2,  Sevgi Keles 1,  Joyce T Hsu 1,  Michel J Massaad 1,  Maria Garcia-Lloret 3,  Rima Hanna-Wakim 4,  Ghassan Dbaibo 4,  Abdullah A Alangari 5,  Abdulrahman Alsultan 5,  Daifulah Al-Zahrani 6,  Raif S Geha 1,  Talal A Chatila 7
Affiliations

Affiliations

  • 1 Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
  • 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, Mass.
  • 3 Division of Immunology, Department of Pediatrics, University of California at Los Angeles, Los Angeles, Calif.
  • 4 Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon.
  • 5 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 6 Immunology and Allergy, Pediatric Department, King Abdulaziz Medical City-WR, Jeddah, Saudi Arabia.
  • 7 Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: [email protected].
PMID: 25468195 DOI: 10.1016/j.jaci.2014.10.019
Abstract

Background: A number of heritable immune dysregulatory diseases result from defects affecting regulatory T (Treg) cell development, function, or both. They include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is caused by mutations in forkhead box P3 (FOXP3), and IPEX-like disorders caused by mutations in IL-2 Receptor α (IL2RA), signal transducer and activator of transcription 5b (STAT5b), and signal transducer and activator of transcription 1 (STAT1). However, the genetic defects underlying many cases of IPEX-like disorders remain unknown.

Objective: We sought to identify the genetic abnormalities in patients with idiopathic IPEX-like disorders.

Methods: We performed whole-exome and targeted gene sequencing and phenotypic and functional analyses of Treg cells.

Results: A child who presented with an IPEX-like syndrome and severe Treg cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), which was previously implicated as a cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked Treg cell depletion; profoundly decreased expression of canonical Treg cell markers, including FOXP3, CD25, Helios, and cytotoxic T lymphocyte-associated antigen 4; and impaired Treg cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production, with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced Treg cells were normal, LRBA-deficient T cells exhibited increased Apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin complexes 1 and 2.

Conclusion: LRBA deficiency is a novel cause of IPEX-like syndrome and Treg cell deficiency associated with metabolic dysfunction and increased Apoptosis of Treg cells.

Keywords

Autoantibodies; LPS-responsive beige-like anchor; T follicular helper cells; T follicular regulatory cells; X-linked syndrome; autoimmunity; enteropathy; forkhead box P3; immune dysregulation; mammalian target of rapamycin complex; polyendocrinopathy; regulatory T cells.

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